Chemotherapy and Hormonal Therapy in Breast Cancer

By- Dr. Satyajeet RathGuided by – Prof. Kamal Sahni

08-11-2016

Chemotherapy

• Chemotherapy• Adjuvant chemotherapy• Neo-adjuvant chemotherapy• Concurrent chemotherapy

• Sequencing of chemotherapy or radiotherapy

• Chemotherapy in metastatic breast cancer

Adjuvant chemotherapy

Evolution of chemotherapy :

• CMF (6 vs 12)

• FAC/FEC & TAC(6)

• 4AC

• Addition of Taxanes (3/4 AC->T)

• Dose dense schedules of Paclitaxel (weekly and two-weekly)

Progress in adjuvant chemotherapy for breast cancer: an overview ; Jesus Anampa*, Della Makower and Joseph A. Sparano et al. BMC Medicine (2015) 13:195

Trial Year Control arm Treatment arm FU (yr) DFS/RFS OS

Bonadonna et al 1976 Surgery alone CMF X 12 20 26% vs 37% 24% vs 47%

NSABP B-13 1996 Surgery alone M-> F 16 63% vs 77% 65% vs 74%NSABP B-19 1996 M -> F CMF 13 73% vs 83% 74% vs 82%NSABP B-23 2001 CMF X 6 ± tam AC X 4 ± tam 8 85% vs 85% 85% vs 86%NCIC MA5 2005 CMF CEF 10 45% vs 52% 58% vs 62%FASG 05 2001 FEC-50 FEC-100 9.2 45% VS 51% 50% VS 55%CALGB 9344 2003 AC AC -> Taxol 5 65% vs 70% 77% vs 80%NSABP B-28 2005 AC AC -> Taxol 5.4 76% vs 72% 85% vs 85%CALGB 9741 2003 AC T or

A T C q 3 wkAC T or A T C q 2wk

4 75% vs 82% 90% vs 92%

BCIRG 001 2005 FAC X 6 TAC X 6 4.5 68% vs 75% 81% vs 87%PACS 01 2006 FEC X 6 FEC X 3 D X 3 5 73% vs 78% 87% vs 91%

US Oncology 9735

2006 AC X 4 TC X 4 6 79% vs 85% 88% vs 84%

HERA 2005 Various 1 yr after chemo 1 86% vs 78% 95% vs 96%BCIRG 006 2011 AC -> T (52 weeks) AC -> T(H) / TCH 5.5 75% vs 84%/81% 87% vs 92%/91%

Bonadonna et al 1976, 2005

To assess the long term effectiveness of adjuvant treatment with cyclophosphamide, methotrexate, and fluorouracil (CMF) in patients with operable breast cancer at risk of relapse, on the basis of three successive randomised trials.

• Bonadonna G, Brusamolino E,, et al. Combination chemotherapy as an adjuvant treatment in operable breast cancer. N Engl J Med. 1976;294:405–10. • Bonadonna G, Moliterni A,, et al. 30 years’ follow up of randomised studies of adjuvant CMF in operable breast cancer: cohort study. BMJ. 2005;330:217.

Adjuvant systemic therapy has long lasting effects even after 30 years, and these are achieved at the cost of minimal long term sequelae

Standard CMF consisted of cyclophosphamide (100 mg/m2 orally from day 1 to 14), methotrexate (40 mg/m2 intravenously on days 1 and 8), and fluorouracil (600 mg/m2 intravenously on days 1 and 8), repeated every four weeks for either six or 12 cycles.

After a median follow up of 28.5 years for the initialstudy, adjuvant CMF was found to reduce the relative risk of relapse significantly ( P = 0.005) and death ( P = 0.04).

Administration of CMF for 12 cycles does not seem superior to a shorter administration of six cycles. In the node negative and oestrogen receptor negative trial, intravenous CMF significantly reduced the relative risk of relapse of disease ( P = 0.009) and death (P = 0.01) at a median follow up of 20 years.

Treatment outcome in the first randomised CMF study after a median observation of 28.5 years. Left: Relapse free survival after surgery alone (179 patients) v CMF (207 patients). Right: Overall survival after surgery alone (179 patients) v CMF (207 patients).

NSABP B-13 and NSABP B-19

J Clin Oncol 1996;14:1982–92.

Compared sequential methotrexate (M) and fluorouracil (F) (M-->F) with surgery (National Surgical Adjuvant Breast and Bowel Project [NSABP] B-13) and cyclophosphamide (C), M, and F with M-->F (NSABP B-19), in patients with estrogen receptor (ER)-negative tumors and negative axillary nodes

A total of 760 patients were randomized to B-13; 1,095 patients with the same eligibility requirements were randomized to B-19. Disease-free survival (DFS), distant disease-free survival (DDFS), and survival were determined using life-table estimates.

A significant benefit in overall DFS (74% v 59%; P < .001) was demonstrated at 8 years in all B-13 patients who received M-->F (69% v 56% [P = .006] in those <or= 49 years of age, and 81% v 63% [P = .002] in those >or= 50 years).

In B-19, through 5 years, an overall DFS advantage (82% v 73%; P < .001) and a borderline survival advantage (88% v 85%; P = .06) were evident with CMF.

The DFS (84% v 72%; P < .001) and survival (89% v 84%; P = .04) benefits from CMF were greater

in women aged <or= 49 years.

M-->F or CMF after lumpectomy and breast irradiation resulted in a low probability of ipsilateral breast tumor recurrence (IBTR).

In B-13, the frequency of IBTR was 2.6% following M-->F versus 13.4% in women treated by lumpectomy; it was 0.6% following CMF in B-19.

NSABP B-13 Sx alone Sx + M-->F P valueDFS 59% 74% <0.001

NSABP B-19 M-->F CMF P valueDFS 72% 84% <0.001

OS 84% 89% 0.06

NSABP B-23Tamoxifen and Chemotherapy for Axillary Node-Negative, Estrogen Receptor–Negative Breast Cancer: Findings From National Surgical Adjuvant Breast and Bowel Project B-23

Fisher B, Anderson S, Tan-Chiu E, Wolmark N, Wickerham DL, Fisher ER, et al. Tamoxifen and chemotherapy for axillary node-negative, estrogen receptor- negative breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-23. J Clin Oncol. 2001;19:931–42.

Patients (n = 2,008) were randomly assigned to CMF plus placebo CMF plus TAM AC plus placebo AC plus TAM. Six cycles of CMF were given for 6 months four cycles of AC were administered for 63 days. TAM was given daily for 5 years. Relapse-free survival (RFS), event-free survival (EFS), and survival (S) were determined by using

life-table estimates

• No significant difference in RFS, EFS, or OS was observed among the four groups through 5 years (P = .96, .8, and .8, respectively),

for those aged ≤ 49 years (P = .97, .5, and .9, respectively), or for those aged ≥ 50 years (P = .7, .6, and .6, respectively).• No significant difference in any outcome was observed when chemotherapy-

treated patients who received placebo were compared with those given TAM.

CMF AC P valueRFS 87% 87% 0.9

EFS 83% 82% 0.6

OS 89% 90% 0.4

NCIC MA5

J Clin Oncol 23:5166-5170, 2005

CEF Cyclophosphamide 75 mg/m2 orally days 1 through 14, Epirubicin 60 mg/m2 intravenously days 1 and 8, Fluorouracil 500 mg/m2 intravenously days 1 and 8 (CEF) or

Between 1989 and 1993710 pre- and perimenopausal women with axillary node–positive breast cancer CMF

Cyclophosphamide 100 mg/m2 orally days 1 through 14, Methotrexate 40 mg/m2 iv days 1 and 8, Fluorouracil 600 mg/m2 iv days 1 and 8).

Primary end point –RFS Secondary end point -OS median follow-up time 59

months statistically significant

improvement in RFS

CMF CEF P value

10-yr RFS 45% 52% 0.007

10-yr OS 58% 62% 0.085

FASG 05

• FEC 50 - fluorouracil 500 mg/m2 , epirubicin 50 mg/m2 , and cyclophosphamide 500 mg/m2 • FEC 100 - fluorouracil 500 mg/m2 , cyclophosphamide 500 mg/m2 , and epirubicin 100 mg/m2

French Adjuvant Study Group. Benefit of a high-dose epirubicin regimen in adjuvant chemotherapy for node-positive breast cancer patients with poor prognostic factors: 5-year follow-up results of French Adjuvant Study Group 05 randomized trial. J Clin Oncol. 2001;19:602–11.

• 565 patients• Median follow-up was 110 months• At the 5-year follow-up of FASG-05, DFS and OS were significantly improved with epirubicin

100 mg/m2 per cycle compared with 50 mg/m2 per cycle as part of the fluorouracil, epirubicin, cyclophosphamide (FEC) regimen

• Treatment with adjuvant FEC 100 demonstrated superior DFS and OS versus FEC 50 at 10 years of follow-up

• FEC 100 is a more optimal regimen for long-term survival in patients with poor prognosis.

FASG 10 year results

FEC 50 FEC 100 P value

10 yr DFS 45.3% 50.7% 0.0810 yr OS 50.0% 54.8% 0.05

FASG 5 year results

FEC 50 FEC 100 P value

5 yr DFS 54.8% 66.3%  0.03

5 yr OS 65.3% 77.4% 0.007

ROLE OF TAXANES

• CALGB 9344/Intergroup 0148• After surgical treatment, 3,121 women with

operable breast cancer and involved lymph nodes

• Node +ve. Stage II-IIIA• 3 X 2 factorial design• Primary end point – DFS• Secondary end point – OS • Median follow up – 69 mnths

Henderson IC, Berry DA, Demetri GD, Cirrincione CT, Goldstein LJ, Martino S, et al. Improved outcomes from adding sequential Paclitaxel but not from escalating Doxorubicin dose in an adjuvant chemotherapy regimen for patients with node-positive primary breast cancer. J Clin Oncol. 2003;21:976–83.

• Adding paclitaxel to the CA combination led to hazard reductions of 17% for recurrence (P - 0.0023) and 18% for death (P - 0.0064)

• No evidence of a doxorubicin dose effect beyond 60 mg/m2/dose

• Each paclitaxel arm performed better than the corresponding CA arm without paclitaxel

• Improvement of 5% in disease-free and 3% in overall survival was evident at 5 years

• The addition of four cycles of paclitaxel after the completion of a standard course of CA improves the disease-free and overall survival of patients with early breast cancer

CA+Paclitaxel CA alone P values

DFS 70% 65% 0.0023

OS 80% 77% 0.0064

• NSABP B-28• Between August 1995 and May 1998, 3,060 patients were randomly assigned

• AC (1,529)• AC followed by PTX [AC 4 PTX] (1,531).

• Post lumpectomy radiotherapy was mandated. • Post mastectomy or regional radiotherapy was prohibited.• Primary end point – DFS• Secondary end point – OS • Median follow-up is 64.6 months.

Mamounas EP, Bryant J, Lembersky B, Fehrenbacher L, Sedlacek SM, Fisher B, et al. Paclitaxel after doxorubicin plus cyclophosphamide as adjuvant chemotherapy for node-positive breast cancer: results from NSABP B-28. J Clin Oncol. 2005;23:3686–96.

The addition of PTX to AC significantly reduced the hazard for DFS event by 17% (P .006).

Subset analysis of the effect of paclitaxel according to hormone receptors or tamoxifen administration did not reveal statistically significant interaction (for DFS, P - .30 and P - .44, respectively).

Addition of PTX to AC resulted in significant improvement in DFS but no significant improvement in OS with acceptable toxicity

AC-> Pacli AC PDFS 76% 72% 0.007

OS 85% 85% 0.46

• BCIRG 001• 1491 women with axillary node-positive breast cancer• Median follow-up of 55 months• Primary end point – DFS• Secondary end point – OS

Nabholtz JM PT, Mackey J, Pienkowski T, Pawlicki M, Guastalla JP, Vogel C, et al. Phase III trial comparing TAC (docetaxel, doxorubicin, cyclophosphamide) with FAC (5-fluorouracil, doxorubicin, cyclophosphamide) in the adjuvant treatment of node positive breast cancer (BC) patients: interim analysis of the BCIRG 001 study. Proc Am Soc Clin Oncol. 2002;21:36a.

• TAC resulted in• 28 % reduction in the risk of relapse (P=0.001) • 30 % decrease in the risk of death (P=0.008)

• 16% had 20% reduction in LVEF

TAC FAC P

DFS 75% 68% 0.001

OS 87% 81% 0.008

• PACS 01 FNCLCC• Pts – 1999 (996-FEC & 1003-FEC-D)• Operable, node-positive, breast cancer • Primary end point - OS• Secondary end point – DFS• Median follow up – 60 mnths

Between June 1997 and March 2000, 1,999 patients with operable node-positive breast cancer

FEC every 21 days for 6 cycles

or 3 cycles of FEC followed by three cycles of docetaxel, both given every 21 days.

Roche H, Fumoleau P, Spielmann M, Canon JL, Delozier T, Serin D, et al. Sequential adjuvant epirubicin-based and docetaxel chemotherapy for node-positive breast cancer patients: the FNCLCC PACS 01 Trial. J Clin Oncol. 2006;24:5664–71.

• 18% reduction in the relative risk of relapse with FEC-D.

• 27% reduction in the relative risk of death

• Sequential adjuvant chemotherapy with FEC followed by docetaxel significantly improves disease free and overall survival in node-positive breast cancer patients and has a favorable safety profile

FEC FEC-D P

5-yr DFS 73.2% 78.4% 0.011

5-yr OS 86.7% 90.7% 0.014

US Oncology 9735 trial

Jones S, Holmes FA, O'Shaughnessy J, Blum JL, Vukelja SJ, McIntyre KJ, et al. Docetaxel with cyclophosphamide is associated with an overall survival benefit compared with doxorubicin and cyclophosphamide: 7-year follow- up of US Oncology Research Trial 9735. J Clin Oncol. 2009;27:1177–83.

• Patients were randomly assigned to receive either • 4 cycles of standard-dose AC (60/600 mg/m2; n 510),• 4 cycles of TC (75/600 mg/m2; n 506), administered by intravenous infusion

every 3 weeks.• Primary end point – DFS• Secondary end pint – OS • Median follow up – 7 yrs

• TC was superior in older patients as well as younger patients.

• There was no interaction of hormone-receptor status or HER-2 status and treatment.

• Older women experienced more febrile neutropenia with TC and more anaemia with AC.

TC AC P

DFS 81% 75% 0.033

OS 87% 82% 0.032

• Node positive , stage II-IIIA• 2 X 2 Factorial design• Primary end point – DFS• Secondary end pint – OS • Median follow up – 36 mtnhs

Evidence for dose dense chemotherapy

Citron M, et al. J Clin Oncol. 2003;21:1431-1439.

Dose dense

3 weekly

P

DFS 82% 75% 0.010

OS 92% 90% 0.013

• The DFS and OS advantages of dose density were not accompanied by an increase in toxicity

• For node +ve disease, there was an advantage for 2-wk vs 3-wk :

• 26% improvement in DFS• 31% improvement in OS

• But it does not differentiate the benefit of dose dense chemo employing AC->T, either of which could possibly be responsible for the improvement in DFS and OS.

• ECOG 1199• 4950 women • Axillary lymph node–positive or high-

risk (tumor stage T1, T2, or T3 and nodal stage N1 or N2) or high-risk, axillary node-negative

• Primary end point – DFS• Secondary end pint – OS • Median follow up – 63.8 mtnhs

Sparano JA, Wang M, Martino S, Jones V, Perez EA, Saphner T, et al. Weekly paclitaxel in the adjuvant treatment of breast cancer. N Engl J Med. 2008;358:1663–71.

P values0.800.250.01

P values0.290.020.006

As compared with standard treatment (3 weekly Paclitaxel), weekly Paclitaxel was associated with significant improvement in DFS and OS.

EBCTCG Overview 1988

• Systematic review of adjuvant chemotherapy trials• Benefit of polychemotherapy (CMF or Anthracycline containing regimens)

seen in women <50 and aged 50-69. This is unaffected by menopausal status, nodal status or tamoxifen use

• 10 year survival improved by about 10% in the <50 age group and about 2-3% in the 50-69 age group

• Subgroup analysis reduction in recurrence in women under age 50 yrs were 40% for ER poor and 33% for ER + cancers.

• For women age 50-69 yrs reduction in recurrence was 30% for ER poor disease compared with 18% for ER + disease.

Early Breast Cancer Trialists’ Collaborative Group. Effects of adjuvant tamoxifen and of cytotoxic therapy on mortality in early breast cancer. An overview of 61 randomized trials among 28,896 women. N Engl J Med. 1988;319:1681–92.

EBCTCG Overview 2005

Early Breast Cancer Trialists’ Collaborative Group. Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet. 2005;365:1687–717.

• Randomised trials of adjuvant chemotherapy or hormonal therapy that began by 1995.• Many trials involved CMF , Anthracycline-based combinations such as FAC or FEC

tamoxifen, or ovarian suppression• None involved taxanes, trastuzumab, raloxifene, or modern aromatase inhibitors.

Benefits of polychemotherapy vs no chemotherapyCohort Rates of recurrence with and

without chemotherapy (%)Absolute benefit (%)

Age < 50 yr, LN- 17.5 vs 27.4 9.9

Age < 50 yr, LN+ 40.6 vs 55.2 14.6

Age 50-69 yr, LN- 14.3 vs 19.6 5.3

Age 50-69 yr, LN+ 36.7 vs 42.6 5.9

• Single-agent chemotherapy or polychemotherapy versus no adjuvant chemotherapy - single-agent chemotherapy regimens reduce recurrence rates and that these polychemotherapy regimens reduce not only recurrence but also mortality from breast cancer (and hence overall mortality)

• Polychemotherapy versus no adjuvant chemotherapy in younger and older women - the differences are highly significant (all 2p-0·00001), but the absolute benefits at 10 or 15 years appear to be about three times as great for younger than for older women

• Indirect comparisons between CMF-based and anthracycline based polychemotherapy - Both among younger and among older women there are no significant differences between the proportional risk reductions (in recurrence or in breast cancer mortality)

• Presence or absence of tamoxifen - Nearly all the evidence on sequential chemoendocrine therapy involved older women, among whom it appeared somewhat more effective than concurrent chemoendocrine treatment, but this comparison is indirect and the difference is not significant

Anthracyclines vs. CMF

6 months of Anthracycline-based polychemotherapy (eg, with FAC or FEC)

Benefit varies according to agereduces the annual breast cancer death rate by about 38% for women < 50 years of ageBy about 20% for those of age 50–69 years

largely irrespective of the use of tamoxifen and of oestrogen receptor (ER) status, nodal status, or other tumour characteristics.

Also confirmed a moderate but significant advantage for Anthracycline based chemotherapy to CMF in trials involving more than 14,000 pts.

EBCTCG 2012 Meta-analysis

Early Breast Cancer Trialists’ Collaborative Group (EBCTCG), Peto R, Davies C, Godwin J, Gray R, Pan HC, et al. Comparisons between different polychemotherapy regimens for early breast cancer: meta-analyses of long-term outcome among 100,000 women in 123 randomised trials. Lancet. 2012;379:432–44.

All randomised trials begun during 1973–2003 of:

• taxane-based versus non-taxane-based regimens • any Anthracycline based regimen versus standard or near-standard CMF• higher versus lower Anthracycline dosage• polychemotherapy versus no adjuvant chemotherapy

Trials comparing four separate cycles of a Taxane to a fixed Anthracycline-based control regimen

Trials with CMF-treated controls showed that standard 4AC and standard CMF were equivalent (2p=0·67), but that Anthracycline-based regimens with substantially higher cumulative dosage than standard 4AC (e.g. CAF or CEF) were superior to standard CMF (2p=0·0004).

Neo-adjuvant chemotherapy

Benefits of preoperative systemic therapy

• Facilitates breast conservation

• Can render inoperable tumors operable

• Provides important prognostic information at an individual patient level based on

response to therapy, particularly in patients with triple- negative and HER2-positive

breast cancer

• Allows time for genetic testing

• Allows time to plan breast reconstruction in patients electing mastectomy

Candidates of Preoperative systemic therapy

• Patients with inoperable breast cancer• Inflammatory breast cancer• Bulky or matted N 2 axillary nodes• N 3 Nodal disease• T 4 disease

• Patients with operable breast cancer• Large primary tumour relative to breast size in a patient who desires breast

conservation

NCCN 2016

PREOPERATIVE SYSTEMIC THERAPY FOR OPERABLE BREAST CANCER

NCCN Guidelines Version 2.2016

PREOPERATIVE SYSTEMIC THERAPY FOR INOPERABLE OR LOCALLY ADVANCED BREAST CANCER (NON-INFLAMMATORY)

• For patients with inoperable breast cancer• Inflammatory breast cancer

Standard of care

Overview of Randomized Trials Comparing Primary Systemic Therapy and Adjuvant Systemic Therapy in the Breast Cancer

No. of pts Chemo regimn

Tumor stage

Path CR% Overall survival

Neoadjuvant adjuvant Follow-up (yr)

NSABP B-18 1523 AC T1-T3 13% 70 69 10.3

EORTC 698 FEC T1c-T4b 4 72 67 9 act

ECTO 880 AT CMF T2-T3 20 90 87 4.2 med

Institut Curie 414 FAC T2-T3 - 60 65 8.8

Royal Marsden

309 MM(M) T0-T4 13 63 70 9.3 med

Bordeaux 272 EVM/MTV T2-T3 - 59 62 10.3

ABCSG-07 398 CMF T1-T3 6 68 64 10 act

• NSABP B-18• Preop vs Postop chemo, 1523 pts• Operable, palpable breast cancer (T1–3 N0–1 M0)• Primary end point – DFS• Secondary point – Downstaging primary+ AxLN, Comparisions of IBTR

NSABP B-18 Trial: Schema

Operable Breast Cancer

•Stratification• Age• Clinical tumor size• Clinical node status

Operation AC x 4+ TAM if >50 yrs.

AC x 4+ TAM if >50 yrs. Operation

1523 pts.T1-3N0-1

Overall survival and disease free survival according to treatment through 9 years of follow-up (Postop postoperative chemotherapy; Preop-preoperative chemotherapy

5yr survival· Path CR = 87%· Clin PR = 68%· Clin NR = 64%

p<0.00010 1 2 3 4 5

50

60

70

80

90

100

path CR

clin PRclin NR

years

dist

ant d

isea

se-fr

eesu

rviv

al (%

)

• Median follow-up of 5 yr • There was no significant difference seen in DFS and OS

(72.3% VS 73.2%) in adjuvant. • Pts with pCR (absence of invasive tumor in breast) had

an OS rate 88.7% which was superior to others

• 2,411 pts. (diagnosis by fine-needle aspiration or core biopsy)

• T1c-T3, N0-N1, M0• Movable in relation to chest wall and skin

• Nodes of any size but not fixed to each other or to adjacent structures

Bear JCO 2003

Role of taxane to AC preoperatively

No significant difference in DFS or OS

EORTC 10902

JCO November 15, 2001 vol. 19 no. 22 4224-4237

To evaluate whether preoperative neoadjuvant chemotherapy in patients with primary operable breast cancer results in better overall survival (OS) and relapse-free survival rates and whether preoperative chemotherapy permits more breast-conserving surgery procedures than postoperative chemotherapy

• 698 breast cancer patients (T1c, T2, T3, T4b, N0 to 1, and M0)

• Four cycles of fluorouracil, epirubicin, and cyclophosphamide (FEC) administered preoperatively versus the same regimen administered postoperatively

• Primary end point –PFS

• Median follow-up of 56 months

• No significant difference in terms of• OS (hazards ratio, 1.16; P = .38), • PFS (hazards ratio, 1.15; P = .27),• LRR (hazards ratio, 1.13; P = .61).

Cochrane review 2012

Cochrane Database of Systematic Reviews 2012, Issue 2. Art. No.: CD005002.

14 eligible studies which randomised a total of 5,500 women. Women with operable breast cancer: TNM stage T1c, T2, T3, N0 to 2, and M0 (AJCC stage I-IIIA). No restrictions to age or menopausal status. TNM classification (Tumour, Node, Metastasis) is the global standard in

cancer staging Median follow-up ranged from 18 to 124 months

Primary outcomes:- overall survival- disease-free survival- loco-regional recurrence as first event

There was no detectabledifference between preoperative and postoperative chemotherapywith a HR of 0.98 (95% CI, 0.87 to 1.09; P, 0.67)

Comparable overall and disease-free survival rates for preoperative and post-operative chemotherapy, although a higher loco-regional recurrence rate for patients receiving preoperative chemotherapy

Time to locoregional recurrencestatistically significant difference in favour of postoperative chemotherapy with HR of 1.21 (95%CI,1.02 to 1.43; P, 0.03)

• Disease-free survival• Ten studies reported disease-free

survival data on 4510 randomised women involving 1596 estimated events.

• There was no detectable difference between preoperative and postoperative chemotherapy with a HR of 0.97 (95% CI, 0.89 to 1.07; P, 0.58) and with moderate heterogeneity across studies (I2, 32.5%; P, 0.15)

Sequencing of post-op chemotherapy or radiotherapy

Bellon et al (2005)

J Clin Oncol 23:1934-1940. 2005

234 patients were randomly assigned after conservative breast surgery to CT-first receive 12 weeks of cyclophosphamide, doxorubicin, methotrexate, fluorouracil, and prednisone

(CAMFP) before RT or RT-first ( 12 weeks of same chemotherapy after RT)Median follow-up for surviving patients was 135 months

No statistically significant difference inIpsilateral breast cancer recurrence contralateral breast cancer second malignancy and death .10-yr rate of Distant metastasis were 35% and 36%.

P – 0.70

P – 0.41

Concurrent chemotherapy

Study No. of pts

Follow-up (median yr)

Type of chemo

Local control Toxicities with con-CRT

Con-CRT Non-CRT P

Haffty et al 635 8.8 CMF 92 83 <.001 Cosmetic results, toxicities and long term complications are accepteble

Rousse et al 416 5.25 FNC for CRT, FEC for sequential arm

97 91 .01 Febrile neutropenia and grade 3-4 leukopenia significantly more frequent

Toledano et al (ARCOSEIN)

716 6.7 CNF - - - Increased incidence of grade 2 or late toxicities

Arcangeli et al 206 5.4 CMF 97 96 NS Late toxicities and Cosmesis not available yet

• Rouesse et al showed a 2.8-fold increased risk of locoregional recurrence in the subgroup of patients treated with BCS and randomly assigned to the sequential arm

• Arcangeli et al showed no difference in local recurrence rates according to sequence • No detectable diifference in primary end points of any of these trials

ARCOSEIN Trial

J Clin Oncol 25:405-410. 2007

Between February 1996 and April 2000, 716 patients with stages I and II breast cancer

• The CT regimen consisted of mitoxantrone (12 mg/m2), fluorouracil(500 mg/m2), and cyclophosphamide (500 mg/m2) on day 1, and it was repeated every 21 days for six courses.

• In the sequential arm, RT started 3 to 5 weeks after the sixth cycle of CT.• In the concurrent arm, RT started the day of the first CT cycle.• Median FU – 60 mnths• Adjuvant treatment began within 6 weeks after surgery • Primary end point - DFS

• No statistically significant difference in treatment in the 5-year DFS (80% in both groups; P - .83)

• Metastasis-free survival (87% in sequential v 84% in concurrent; P .55), or overall survival (90% in sequential v 91% in concurrent; P - .76).

Sequential Concurrent P valueDFS 80% 80% 0.83LRFS 92% 95% 0.76 DMFS 87% 84% 0.55OS 90% 91% 0.76

Locoregional recurrence-free survival in the (A) node-positive subgroup and in the (B) node-negative subgroup.

In the node-positive subgroup, the 5-year LRFS was statistically better in the concurrent arm (97% in concurrent v 91% in sequential; P .02)

Although the local control was slightly superior in the concurrent chemotherapy arm, subcutaneous fibrosis telangiectasia skin pigmentation breast atrophy were significantly increased in concurrent arm.

Metastatic breast cancer

• Defined by tumor spread beyond the breast, chest wall and regional lymph nodes.• Tumor dissemination can occur through blood and lymphatic vessel and via direct

extension through chest wall.• The most common sites are – Bone, lung, liver, lymph nodes, chest wall and brain.

Treatment goal

• Palliation of sign and symptoms. • Control of tumor burden.• Maintenance of quality of life and function.

Prognostic Factors in Patients With Metastatic Breast Cancer

Prognostic factor Favorable UnfavorablePerformance status Good Poor

Sites of disease Bone, soft tissue Viscera, CNS

No. of sites of disease Few Multiple

Hormone receptor status Positive Negative

Her-2/neu status NegativePositive (significance less clear in Her-2/neu inhibitors era)

Disease-free interval >2 years <2 years

Systemic Treatment Approach for Metastatic Breast Cancer

Metastatic Breast Cancer

• Limited metastases (bone & soft tissue)• Positive hormone receptors• Disease-free interval 2 years

• Extensive disease or visceral crisis• Negative hormone receptors• No response to hormones

Hormonal Therapy Chemotherapy

Response No responseNo progression Progression of disease

If disease progresses, second-line hormonal therapy Second-line chemotherapy

Role of Chemotherapy in metastatic breast cancer

CHEMOTHERAPY REGIMENS FOR RECURRENT OR METASTATIC BREAST CANCER

NCCN Guidelines Version 2.2016

NICE clinical guideline 2014

• For patients with Metastatic breast cancer who are not suitable for Anthracyclines (because they are contraindicated or because of prior Anthracycline treatment either in the adjuvant or metastatic setting), systemic chemotherapy should be offered in the following sequence:

First line: single-agent docetaxelSecond line: single-agent vinorelabine or capecitabineThird line: single-agent capecitabine or vinorelabine (whichever was not used as

second-line treatment).

• Evaluate the effect of different first-line chemotherapy durations in patients with metastatic breast cancer (MBC) on overall survival (OS) and progression-free survival (PFS)

• 11 randomized clinical trials including 2,269 patients • Longer first-line chemotherapy duration resulted into a significantly improved OS

(hazard ratio [HR], 0.91; 95% CI, 0.84 to 0.99; P .046) and PFS (HR, 0.64; 95% CI, 0.55 to 0.76; P .001).

• Longer first-line chemotherapy duration is associated with marginally longer OS and a substantially longer PFS.

Single vs Combination chemotherapy • In the Eastern Cooperative Group (ECOG) 1193 trial • 700 women were randomly assigned to doxorubicin plus paclitaxel (AP), doxorubicin, or paclitaxel Treatment with AP resulted in:• A higher overall response rate (ORR) compared with doxorubicin or to paclitaxel (47

versus 36 and 34 percent)• A longer median time to progression (TTP; 8 versus 6 and 6 months) (p value .011)• However, there was no difference in overall survival (OS; 22 versus 19 and 22 months)

Taxane vs taxane plus Anthracyclines

J Clin Oncol 26:1980-1986. © 2008

• Individual patient data were collected on eight randomized combination trials comparing Anthracyclines plus Taxanes with Anthracyclines + cyclophosphamide

• Three single-agent trials comparing Taxanes with Anthracyclines.• Combination trials included 3,034 patients; single-agent trials included 919 patients.

Median follow-up of living patients was 43 months, Median survival was 19.3 months, and median PFS was 7.1 months. In single-agent trials, response rates were similar in the Taxanes (38%) and in the Anthracyclines (33%)

arms (P .08). In combination trials, response rates were 57% (10% complete) in taxane-based combinations and 46% (6% complete) in control arms (P .001).

Combination: capecitabine + Docetaxel

Patients were randomized to 21-day cycles of oral capecitabine 1,250 mg/m(2) twice daily on days 1 to 14

plus docetaxel 75 mg/m(2) on day 1 (n = 255) or Docetaxel 100 mg/m(2) on day 1 (n = 256).

Capecitabine/docetaxel resulted in significantly superior efficacy in time to disease progression (TTP)( P =.0001; median, 6.1 v 4.2 months), overall survival (P =.0126; median, 14.5 v 11.5 months), objective tumor response rate (42% v 30%, P =.006) compared with docetaxel.

Combination: Capecitabine + Docetaxel vs Gemcitabine + docetaxel

Patients were randomly assigned to GD (G 1,000 mg/m2 days 1 and 8; D 75 mg/m2 day 1) or CD (C 1,250 mg/m2 twice daily days 1 through 14; D 75 mg/m2 day 1) every 21 days. Comparison of progression-free survival (PFS) was the primary objective.

J Clin Oncol 27:1753-1760. © 2009

No difference was observed between GD and CD arms in PFS, ORR, and OS. TTF was longer in the GD arm. nonhematologic toxicity profile that favors GD over approved doses of CD, suggest that gemcitabine may be a better option than capecitabine in combination with docetaxel in this

clinical setting.

Combination: Ixabepilone + capecitabine

Clin Oncol 25:5210-5217. © 2007

752 patients were randomly assigned to Ixabepilone 40 mg/m2 intravenously on day 1 of a 21-day cycle plus capecitabine 2,000 mg/m2

orally on days 1 through 14 of a 21-day cycle, or capecitabine alone 2,500 mg/m2 on the same schedule,The primary end point was progression-free survival

Ixabepilone plus capecitabineprolonged progression-free survival relative to capecitabine (median,5.8 v 4.2 months), with a 25% reduction in the estimated risk of disease progression (hazard ratio, 0.75; 95% CI, 0.64 to 0.88; P .0003)

Specific sites of metastases: bone and brain

A bone modifying agent (bisphosphonate or denosumab) should be routinely used in combination with other systemic therapy in patients with MBC and bone metastases.

Radiological assessments are required in patients with persistent and localized pain due to bone metastases to determine whether there are impending or actual pathological fractures.

• If a fracture of a long bone is likely or has occurred, an orthopaedic assessment is required as the treatment of choice may be surgical stabilization, which is generally followed by radiotherapy (RT).

• In the absence of a clear fracture, RT is the treatment of choice.

ESO-ESMO 2nd international consensus guidelines for advanced breast cancer (ABC2) Annals of Oncology 00: 1–18, 2014

Hormone Therapy

Time Line

Drugs Targeting Estrogen and It’s Receptor in Breast Cancer

Estrogen

Cell Growth and Division

Estrogen Receptor

SERMS (tamoxifen, raloxifene), SERDS (fulvstrant)

Aromatase inhibitors, ovarian suppression

Rationale for receptor based Rx• Response rates to endocrine manipulation in ER +ve patients was as high as 53% ( only 6% in ER –ve) –

Whitliff et al.

• Receptors correlate with other prognostic markers:• Cellular turnover rates, • Nuclear grade, and • Degree of histologic differentiation

• Receptor positivity also correlates with:• Disease-free interval• Decreasing tumor size

• Prolongation of DFS is independent of menopausal status, tumor size, and nodal status.

Wittliff JL. Specific receptors of the steroid hormones in breast cancer. Semin Oncol 1984;1:109–118

Endocrine therapies

• Selective Estrogen Receptor Modulators:

• Tamoxifen• Torimefene

• Androgens• Fluoxymesterone

• Progestins• Megestrol acetate• Medroxyprogesterone acetate

• High dose Estrogens

• Aromatase inhibitors:• Letrozole• Anastrazole• Exemestane

• Steroidal Antiestrogens (SERD):• Fulvestrant

• LHRH agonists• Leuprolide• Goserelin

• GnRH Agonists• Triptorelin

• Gland ablation• Ovary• Pituitary• Adrenals

Mechanism of action

• All endocrine therapies target the estrogen receptor at one level or other.

• While the PR receptor doesn't act as a target directly it does indicate a functional ER pathway as it is a ER induced gene.

SERM

• The SERMs are chemically diverse compounds that lack the steroid structure of estrogens but possess a tertiary structure that allows them to bind to the estrogen receptor.

• Examples:• Tamoxifen• Raloxifen• Tormifen

• Selective modulation explained by:• Differential estrogen-receptor expression in a given target tissue• Differential estrogen-receptor conformation on ligand binding • Differential expression and binding to the estrogen receptor of coregulator proteins

Tamoxifen• Chemically a triphenylethylene.• MOA: Competitive binding to the estrogen receptor

resulting in reduction of transcription of estrogen regulated genes.

• Dimethylaminoethoxy side chain and the trans configuration are crucial for the antiestrogenic activity of tamoxifen

• The net result is a block in the G1 phase of the cell cycle and a slowing of cell proliferation.

• Tamoxifen is thus, a cytostatic drug.

Pharmacokinetics

• Long t1/2 : 7 -14 days.• OD dose can be used• Reduced bioavailability is not a cause for resistance.

• Metabolism in liver and excretion in feces ► Renal dysfunction not a contraindication.

• Metabolized by CYP 450 3A4 enzyme:• Can reduce warfarin metabolism.• Careful INR monitoring needed in patients receiving warfarin with tamoxifen.

Aromatase Inhibitors

• Capable of selective estrogen deprivation without impairment of adrenal androgen synthesis.

• Two types exist:• Type I : Enzyme inactivators (Steroidal)• Type II : Competitive antagonists ( Non steroidal)

• 3 generations exist:• 1st generation: Aminoglutethemide• 2nd generation: Formestane (Type I) , Fadrazole• 3rd generation: Exemestane (Type I) , Anastrazole , Letrozole,

3rd generation AI• These drugs inhibit the Aromatase enzyme

selectively by blocking the heme moiety of the enzyme.

• 3rd generation AIs are 3 times more potent than aminoglutethemide.

• Dose:• Letrozole (Femara) – 2.5 mg OD• Anastrazole (Arimidex) – 1 mg OD• Exemestane (Aromasin) – 25 mg OD

Letrozole

Anastrazole

Special Properties

• Anastrazole: • Less than 10% of the drug is cleared as unchanged drug because of its extensive metabolism.

• Letrozole: • Only 5% is excreted in the urine, letrozole can be safely used in patients with renal

insufficiency. • Used with caution when patients have severe liver impairment. • Produces the greatest suppression of estrogen synthesis

• Exemestane:• Weakly androgenic metabolite (17-hydroexemestane) that may ameliorate bone loss

associated with estrogen deprivation

Fulvestrant• Classified as a SERD.• Considerably higher affinity for ER than

tamoxifen • Promotes accelerated ER turnover,• Suppression of ER protein levels,• Inhibition of ER dimerization,• Reduced shuttling of the ER from the cytoplasm to the

nucleus

• Developed for clinical use as a 250-mg intramuscular monthly depot injection

• Developed to counter the estrogenic effects of Tamoxifen on uterus and the bone related effects of AIs.

Tamoxifen

Background• The gold standard of treatment in the adjuvant setup is tamoxifen.• Adjuvant Tamoxifen has been used for treating breast cancer since 1970s• Some authors have attributed the 25% reduction in breast cancer mortality in

western countries over the past decade to tamoxifen use.• Issues that need to be answered are:

• Optimal duration and dose• Patient selection criteria• Combination with chemotherapy• Risks of tamoxifen therapy• Additional benefits of tamoxifen therapy• Place of the newer agents like AIs

Evolution of Endocrine therapy

• 2 yr Tamoxifen

• 2 yr vs 5 yr Tamoxifen

• 5 yr vs 10 yr Tamoxifen

• AIs (Exemestane, Anastrozole, Letrozole)

• Sequential vs Upfront

• Addition of OFS to AIs in Premenopausal

Adjuvant Tamoxifen alone (Benefit of 2yrs Tam)• Several trials have demonstrated that tamoxifen adds significantly to the DFS in the

adjuvant setting.• Two major trials have also demonstrated a OS benefit

Trial Dose Duration DFS OS

NATO 20 2 P < 0.05 P < 0.05

Christie 20 1 P < 0.05 NS

Stockholm 30 2 P < 0.05 NS

CRC 20 2 P < 0.01 NS

Scottish 20 5 P < 0.05 P < 0.05

• NATO. Controlled trial of tamoxifen as a single adjuvant agent in the management of early breast cancer. “Nolvadex” Adjuvant Trial Organisation. Br J Cancer 1988;57:608–611. • Breast Cancer Trials Committee. Adjuvant tamoxifen in the management of operable breast cancer: the Scottish Trial. Report from the Breast Cancer Trials Committee, Scottish Cancer

rials Office (MRC), Edinburgh. Lancet 1987;2:171–175.

Overall benefits of tamoxifen Rx

Reduction in Annual Odds ± SE

Years Recurrence Death

0–1 53 ± 5 22 ± 10

2–4 42 ± 5 29 ± 6

5–9 31 ± 6 29 ± 5

• While the patients are on tamoxifen:1 of every 2 recurrences and 1 of every 3 deaths are avoided by the

tamoxifen therapy.

• Tamoxifen continues to demonstrate further reductions in the odds of recurrence and death in years 5 through 9.

• This is called the “carryover effect”

Tamoxifen for early breast cancer: an overview of the randomised trials Early Breast Cancer Trialists’ Collaborative Group Lancet 1998; 351: 1451–67

Absolute risk reductions during the first 10 years, subdivided by tamoxifen duration and by nodal status (after exclusion of women with ER-poor disease)

Conclusions from EBCTCG 1998

• Among the 18,000 women with ER-positive tumours , the proportional reductions in the recurrence rates in the trials of 1 year, 2 years, and about 5 years of tamoxifen were 21% , 28% , and 50%, respectively

• Among the 2000 women with ER-positive, PR- poor tumours, the recurrence reduction produced by tamoxifen was 32% (2p - 0·00001) and the mortality reduction was 18% (2p - 0·01), which are not materially different from the corresponding reductions of 37% (2p - 0·00001) and 16% (2p -0·00001) among the 7000 women with ER-positive, PR-positive tumours

• Among the 2000 women with ER-poor, PR- poor tumours, tamoxifen had no apparent effect on recurrence or mortality rates (1% reduction in both cases), whereas among the 602 women with ER- poor, PR-positive tumours, the recurrence reduction was 23% (2p=0·05) and the mortality reduction was 9% (NS)

Optimal Duration of Tamoxifen Rx

Reduction in recurrences Reduction in deaths

Tamoxifen ~ 1 yr 18% ± 3 11% ± 3Tamoxifen ~ 2 yr 24% ± 2 14% ± 2Tamoxifen ~ 5 yr 43% ± 3 23% ± 4

In the EBCTCG meta-analysis 5 yr tamoxifen reduced the risk of recurrence and death twice as much as 2 yr tamoxifen therapy.

In two large European trials from Britain and Sweden, women treated with tamoxifen for 5 years, had fewer recurrences and deaths than those treated for only 2 years.

Swedish Breast Cancer Cooperative Group. Randomized trial of two versus five years of adjuvant tamoxifen for postmenopausal early stage breast cancer. Swedish Breast Cancer Cooperative Group. J Natl Cancer Inst 1996;88:1543–1549

Dose of tamoxifen

• 20 mg once daily dose of tamoxifen is the standard dose.• Higher doses are not more effective• Also lead to greater incidence of side effects.

Bratherton DG, et al. A comparison of two doses of tamoxifen (Nolvadex) in postmenopausal women with advanced breast cancer: l0 MG BD versus 20 MG BD. Br J Cancer 1984;50:199

Goldhirsch A, Joss RA, Leuenberger U, Cavalli F, Ryssel HJ, Brunner KW. An evaluation of tamoxifen dose escalation in advanced breast cancer. Am J Clin Oncol 1982;5:501.

Tamoxifen & ER status

• ER receptor –ve tumors in tissue cultures are non responsive to tamoxifen therapy.

• However problems interpreting the results of tamoxifen therapy in ER –ve tumors are:Variable assay quality and reference valuesVariable assay sensitivityPossible paracrine loop action of tamoxifen (Few ER +ve tumors affecting surrounding ER –ve

tumors)Systemic effects of Tamoxifen (e.g. IGF -1 concentrations)

• The low response rates observed with tamoxifen in ER -ve metastatic disease (5% to 10%) argue that these ancillary effects of tamoxifen are clinically unimportant

Tamoxifen & ER status• Most of the trials and meta-analyses have demonstrated no benefit of adjuvant

tamoxifen in ER -ve tumors.

• Three trials however showed some benefit:NATO study:

When 5 fmol/mg was taken as a cut off point beneficial effect of tamoxifen was equal in both ER +ve and –ve tumors.

Scottish trial: Showed that even in ER –ve tumors there was a increase in DFS over control group.

NSABP B-09 trial: some women aged 60 to 70 years received benefit from tamoxifen even if their tumor had an ER content of 0 to 9 fmol per mg protein

• However NSABP B-23 trials which compared tamoxifen alone in ER-ve, node negative patients no survival benefit could be demonstrated for 5 yrs tamoxifen therapy.

Tamoxifen & PR status

• Effect of PR status:• It is believed that in ER –ve , PR +ve patients may be more responsive to tamoxifen

therapy.• Results are interpolated from results in metastatic disease.• In a retrospective analysis patients who were both ER and PR +ve, fared better than

patients who were ER +ve and PR –ve • 53% reduction* in risk of recurrence for patients who were ER & PR +ve.• In patients who were ER +ve only the risk was reduced* by 23% only.

• The lesser benefit of Tamoxifen in patients with ER +ve but PR –ve tumors has also been confirmed in the ATAC trial .

Bardou VJ, Arpino G, Elledge RM, et al. Progesterone receptor status significantly improves outcome prediction over estrogen receptor status alone for adjuvant endocrine therapy in two large breast cancer databases. J Clin Oncol 2003;21:1973–1979 .

Tamoxifen & Menopausal status

• Initially believed to have lesser efficacy in premenopausal women.

• Many trials gave tamoxifen for 2 years.• Greater proportion of premenopausal

women have ER –ve tumors.

• Recent trials have revealed a substantial benefit in terms of:

Long term survivalRecurrence rates

Reduction of odds of

recurrence

Absolute reduction at 10 yrs

Age 0-4 yrs 5-9 yrs

<50 42% 22% 10.7%

50+ 49% 33% 14.6%

Reduction of odds of deaths

Absolute reduction at 10 yrsAge 0-4 yrs 5-9 yrs

<50 31% 28% 6.8%

50+ 32% 36% 8.2%

TAMOXIFEN RESULTS BY YEARS OF FOLLOW-UP; ER-POSITIVE OR UNKNOWN PATIENTS TREATED FOR 5 YEARS–OVERVIEW 2004

Tamoxifen & nodal statusReduction in Annual Odds*

Recurrence Cancer Deaths

Any Deaths

Node negative0 – 4 yrs 48% 33% 25%5 + yrs 35% 30% 21%

Node Positive0 – 4 yrs 41% 40% 29% 5 + yrs 20% 38% 36%• At 10 yrs:

The recurrence rates were reduced by 14% and 11% in node –ve and +ve patients respectively.

Similarly, mortality reduced by 14.8% and 12% respectively.

Tamoxifen for early breast cancer: an overview of the randomised trials Early Breast Cancer Trialists’ Collaborative Group Lancet 1998; 351: 1451–67

• ATLAS• 12894 women, Early Breast Ca• 7.6 yrs FU• Had completed 5 years of treatment with tamoxifen were randomly allocated to

continue tamoxifen to 10 years or stop at 5 years • When ATLAS began in 1996, 2 years and 5 years of tamoxifen were both standard treatment

options

5 yrs vs 10 yrs Tamoxifen

Davies et al, Lancet 2012

• Among women with ER-positive disease, allocation to continue tamoxifen • reduced the risk of breast cancer recurrence (617 recurrences in 3428 women allocated to continue vs

711 in 3418 controls, p=0·002), • reduced breast cancer mortality (331 deaths vs 397 deaths, p=0·01), and • reduced overall mortality (639 deaths vs 722 deaths, p=0·01).

• Recurrence and breast cancer mortality during the second decade after diagnosis are reduced more effectively by 10 years of adjuvant tamoxifen than by 5 years.

• Taken together with the results from trials of 5 years of tamoxifen versus none, the results from ATLAS show that 10 years of effective endocrine therapy can approximately halve breast cancer mortality during years 10–14 after diagnosis.

• The cumulative risk of endometrial cancer during years 5–14 was 3·1% for women allocated to continue versus 1·6% for controls

• ATLAS• ATTom• E4181• NSABP B 14• Scottish Trial

Al-Mubarak M, Tibau A, Templeton AJ, Cescon DW, Ocana A, et al. (2014) Extended Adjuvant Tamoxifen for Early Breast Cancer: A Meta-Analysis. PLoS ONE 9(2): e88238

• Five trials comprising 21,554 patients

• Extended adjuvant tamoxifen was not associated with a significant reduction in the risk of recurrence (OR:0.89, 95% CI 0.76–1.05, p=0.17)

• There was no association between extended adjuvant tamoxifen and all-cause of death (OR:0.99, 95% CI 0.84–1.16, p = 0.88)

• There was no apparent difference in the effect between pre- and post-menopausal patients.

• Endometrial carcinoma was substantially more frequent with extended adjuvant tamoxifen (OR:2.06, 95% CI 1.65–2.58, p-0.001, number needed to harm:89)

• Davies C, Pan H, Godwin J, Gray R, Arriagada R, et al. (2012) Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial. Lancet 4: 61963–61961.

• Gray RG, Rea D, Handley D, Bowden SJ, Perry P (2013) aTTom: Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years in 6,953 women with early breast cancer. J Clin Oncol 31, 2013 (suppl; abstr 5).

• Fisher B, Dignam J, Bryant J, Wolmark N (2001) Five versus more than five years of tamoxifen for lymph node-negative breast cancer: updated findings from the National Surgical Adjuvant Breast and Bowel Project B-14 randomized trial. J Natl Cancer Inst 93: 684–690.

• Stewart HJ, Prescott RJ, Forrest AP (2001) Scottish adjuvant tamoxifen trial: a randomized study updated to 15 years. J Natl Cancer Inst 93: 456–462.

• Tormey DC, Gray R, Falkson HC (1996) Postchemotherapy adjuvant tamoxifen therapy beyond five years in patients with lymph node-positive breast cancer. Eastern Cooperative Oncology Group. J Natl Cancer Inst 88: 1828–1833.

• Forest plots of odds ratios for breast cancer recurrence in node negative and in node positive patients with extended adjuvant tamoxifen (.5 years) versus adjuvant tamoxifen (5 years) based on primary analysis of individual trials. Odds ratios for each trial are represented by the squares, the size of the square represents the weight of the trial in the meta-analysis, and the horizontal line crossing the square represents the 95% confidence interval. The diamonds represent the estimated pooled effect based for each cohort individually (labeled subtotal) and for all cohorts together (labeled total).

Major studies comparing adjuvant therapy incorporating AIs with 5 yrs Tamoxifen

1. Upfronta. ATAC - Anastrozoleb. BIG-198 - Letrozole

2. Sequential (after 2-3 yrs of Tamxifen)a. IES - Exemestaneb. ARNO/ABCSG - Anastrozole

3. Extended (after 5 yrs of Tamoxifen)a. MA-17 - Letrozoleb. NSABP B-33 - Exemestane

AI in adjuvant setting• 7 trials have been reported all of which involve post menopausal females with HR +ve disease.• A theoretical priming benefit initial tamoxifen made many trials use tamoxifen in initial 2-3 yrs

prior to witching over to tamoxifen.

Trial Yrs Tmx N FU (mo) DFS OSMA 17 (Let)* 5 5157 30 2.4% NAATAC (Ana) 0 6186 68 2.4% 0.3%BIG 01-98 (Let) 0 8010 26 1.9% 0.7%ABCSG/ARNO (Ana) 2 3224 28 2.4% NAITA (Ana) 2 426 24 7.1% NAIES (Exe) 2-3 4742 31 3.5% 0.6%

* Placebo controlled

• ATAC - Arimidex, Tamoxifen, Alone or in Combination • ATAC, now known as LATTE (Long-term Anastrozole versus Tamoxifen Treatment Effects)

• Anastrozole (1 mg) with tamoxifen (20 mg), both given orally every day for 5 years, as adjuvant treatment for postmenopausal women with early-stage breast cancer.

• Primary endpoint of disease-free survival• Secondary endpoints of time to recurrence, time to distant recurrence, incidence of

new contralateral breast cancer, overall survival, and death with or without recurrence

• Randomised patients (anastrozole n=3125, tamoxifen n=3116) and hormone-receptor-positive patients (anastrozole n=2618, tamoxifen n=2598)

• Median fu – 120 mth

• Tamoxifen has shown a carryover benefit for recurrence in the first 5 years after treatment, but not after that.

• Carryover effect for recurrence was larger for anastrozole than for tamoxifen in the present study and remained significant for the entire 10-year follow-up period

• The additional benefit beyond that achieved with tamoxifen might be waning after about 8 years, and further follow- up is needed to see how long this effect will be maintained with anastrozole

• First trial to show that an aromatase inhibitor is more effective and has fewer serious side-effects than tamoxifen in the adjuvant setting

• Confirm the long-term superior efficacy and safety of anastrozole over tamoxifen as initial adjuvant therapy for postmenopausal women with hormone-sensitive early breast cancer.

• BIG-198• Compared letrozole with tamoxifen as adjuvant treatment for steroid-hormone-

receptor–positive breast cancer in postmenopausal women. • Compared five years of treatment with various adjuvant endocrine therapy regimens

in postmenopausal women with hormone-receptor–positive breast cancer: letrozole, letrozole followed by tamoxifen, tamoxifen, and tamoxifen followed by letrozole.

• 8010 women• Median FU – 25.8 mth• Primary end point – DFS• Secondary end point – OS, Systemic-disease free survival

• In postmenopausal women with endocrine-responsive breast cancer, adjuvant treatment with letrozole, as compared with tamoxifen, reduced the risk of recurrent disease, especially at distant sites

Side-effect profile

• As first-line treatment for metastatic breast cancer, third-generation aromatase inhibitors are equivalent or superior to tamoxifen , with a favourable safety profile.

• Fractures were significantly more frequent in the letrozole group than in the tamoxifen group (5.7 percent vs. 4.0 percent, P<0.001)

• As compared with tamoxifen, letrozole was associated with • fewer thromboembolic events (1.5 percent vs. 3.5 percent, P<0.001),• lower rate of vaginal bleeding (3.3 percent vs. 6.6 percent, P<0.001), • fewer endometrial biopsies (72 of 3089 women [2.3 percent] vs. 288 of 3157 women [9.1 percent],

P<0.001), and • fewer invasive endometrial cancers (4 of 3089 women [0.1 percent] vs. 10 of 3157 women [0.3

percent], P = 0.18).

• The overall incidence of adverse cardiovascular events of grade 3, 4, or 5 was similar in the two groups (3.7 percent in the letrozole group and 4.2 percent in the tamoxifen group)

Positive results reported in other trials of letrozole as adjuvant treatment for hormone-receptor–positive breast cancer in postmenopausal women• BIG 1-98• ILBCG• Goss et al• Ellis et al

1. Mouridsen H, Gershanovich M, Sun Y, et al. Superior efficacy of letrozole ver-sus tamoxifen as first-line therapy for postmenopausal women with advanced breast cancer: results of a phase III study of the International Letrozole Breast Can- cer Group. J Clin Oncol 2001;19:2596-606. [Erratum, J Clin Oncol 2001;19:3302.]

2. Mouridsen H, Gershanovich M, Sun Y, et al. Phase III study of letrozole versus tamoxifen as first-line therapy of advanced breast cancer in postmenopausal women: analysis of survival and update of efficacy from the International Letrozole Breast Cancer Group. J Clin Oncol 2003;21:2101- 9.

3. Goss PE, Ingle JN, Martino S, et al. A randomized trial of letrozole in post- menopausal women after five years of tamoxifen therapy for early-stage breast cancer. N Engl J Med 2003;349:1793-802.

4. Ellis MJ, Coop A, Singh B, et al. Letro- zole is more effective neoadjuvant endo- crine therapy than tamoxifen for ErbB-1 and/or ErbB-2-positive primary breast can- cer: evidence from a phase III randomized trial. J Clin Oncol 2001;19:3808-16.

• 4724 postmenopausal patients• Invasive, oestrogen-receptor-positive or oestrogen-receptor unknown breast cancer who were disease-free on 2–3 years

of tamoxifen• Randomly assigned to switch to exemestane (n=2352) or to continue tamoxifen (n=2372) for the remainder of a 5-year

endocrine treatment period

IES

• Long-term results• Improvement in DFS and OS in

patients who switched to exemestane were sustained, with no evidence 6 years post treatment that these effects were transient

• Primary endpoint DFS• Secondary end point – OS• Median follow-up of 55·7 months

2008

Adjuvant Endocrine Therapy

NCCN Guidelines Version 2.2016

Toxicity of AIs vs Tamoxifen

MA -17 ATAC BIG IES

Vaginal Complications - 1.7% - 14% - 3.3% - 1.5% Tmx poorerEndometrial Cancer NA - 0.6% - 0.4% NA

Thromboembolic events NA - 1.7% - 1.2% - .9%Cardiac complications 0.5% 0% 0.4% NA AI

poorerArthalgia /Myalgia 23% 7% NA 6%Osteoporotic fractures 2.3% 2.2% 1.7& 2%Hot flushes 6% 5% 4% 2%

Since the absolute benefit of using a AI in adjuvant setting over tamoxifen is ~ 2% reduction in recurrence rates and 1.5% reduction in mortality this excess toxicity needs to be balanced against the bone damage produced by AIs in this setting.

Addition of OFS to AIs – SOFT & TEXT Trials

Prudence A. Francis et al., N Engl J Med 2015;372:436-46SOFT Trial

Olivia Pagani et al., N Engl J Med 2014;371:107-18SOFT + TEXT Trial

Adjuvant Ovarian Supression in Premenopausal Breast Cancer

Adjuvant Exemestane with Ovarian Supression in Premenopausal Breast Cancer

Primary end point of both RCT - DFS

SOFT Tamoxifen-OFS Tamoxifen P value

5-yr DFS 86.6% 84.7% 0.10

5-yr OS 96.7% 95.1% 0.13

5-yr BC freedom rate 88.4% 86.4% 0.09

TEXT-SOFT combined analysis

Tamoxifen-OFS Exemestane-OFS P-value

5-yr DFS 87.3% 91.1% P<0.0015-yr BC free interval 88.8% 92.8% P<0.001Freedom from recurrence of breast cancer at a distant site

92% 93.8% P=0.02

5-yr OS 95.9% 96.9% p=0.37Selected adverse events of Grade 3 or 4

29.4% 30.6%

AI : 1st line therapy• 3 major phase III trials have directly compared tamoxifen against AI.• All have shown an improvement in time to progression (TTP)• The study by the International Letrozole Breast Cancer Group is the largest in the series.

Trial Drug N RR TTP (mo) CommentNabholtz et al Ana 353 21% 11.1* Retrospective

analysis revealed longer TTP with Anastrazole after combining these

two trials

Tmx 17.7% 5.6TARGET trail Ana 668 32.9% 8.2

Tmx 32.6% 8.3Mouridsen et al

Let 907 30% 9.4Tmx 20% 6.0

AI : 1st line therapy• Several trials have shown that the TTP is significantly improved in metastatic breast cancer

when AI are used as 1st line therapy instead of tamoxifen.

• The impact on OS not clear however.

• In the trail comparing Letrozole to Tamoxifen it was shown that OS improved in the first 2 yrs.

• However no benefit exists at 5yrs.

• However due to crossing over a significant impact on OS may have been lost.

• Crossing over to Tamoxifen after initial AI therapy may be theoretically unwise as:

• Estrogen deprived cancer cells may be become paradoxically sensitive to tamoxifen.

AI : 2nd Line therapy

• Initially used instead of high dose steroid in tamoxifen resistant patients.

• Showed a small but significant benefit in 5 RCTs in terms of survival and better side effect profile

• However overall the response rates were in the 10% to 20% range

• Significant clinical benefit from Aromatase inhibitors often occurs in the absence of dramatic disease regression.

• Therefore now the standard 2nd line endocrine therapy in tamoxifen resistant metastatic breast cancer.

Results: AIs as 2nd line Rx

Trial Drug N RR TTP (mo) OS (mo)Anastrazole vs Megestrol acetate

Ana (10 mg) 764 8.9 < 21 25.5Ana (1 mg) 10.3 26.7 *Meg (40 mg) 7.9 22.5

Letrozole vs Megestrol acetate

Let (2.5 mg) 551 24 5.6* 25.3*Let (0.5 mg) 13 5.1 21.5Meg (40 mg) 16 5.5 21.5

Letrozole vs Megestrol acetate

Let (2.5 mg) 602 16 3 29Let (0.5 mg) 21 6* 33*Meg (40 mg) 15 3 26

Treatment after progression on AI

• Progression after 1st line AI therapy is difficult to tackle.• A retrospective analysis has shown that objective response after tamoxifen therapy

is of the order of 10% after AI failure.• Another phase II trial has shown that Exemestane may be associated with a

response rate of 6.6% after Letrozole / Anastrazole therapy.• No endocrine therapy is thus available that can give promising results after AI

failure.

Fulvestrant• A potent inhibitor of estrogen-dependent transcription.• In preclinical models, Fulvestrant was found to be effective against tamoxifen-resistant MCF7 cell

xenografts.• In a trial comparing 1st line tamoxifen vs fulvestrant, no advantage was obtained in TTP or overall

response over tamoxifen.• Given easier use of AI / Tamoxifen place in therapy remains questionable.

Trial N Response Rates (%)

Stable Disease ≥ 24 wk (%)

Time to Progression

(mo)

Osborne et al

An400

17.5 18.6 3.4Ful 17.5 24.8 5.4

Howell et al

Ana451

15.7 45 5.1Ful 20.7 44.6 5.4

Endocrine therapy in Neoadjuvant setting

Evaluation in the neoadjuvant setting

• Tamoxifen is not commonly used as neoadjuvant therapy (to shrink breast tumors prior to surgery),

• Because it is perceived as being less efficacious than chemotherapy. • However, the advent of AIs has raised the question of whether more potent endocrine

therapies may be of benefit in this setting, particularly in patients who may be too frail to cope with the side effects of chemotherapy.

• P024- Eiermann W, Paepke S, Appfelstaedt J et al (2001) Preoperative treatment of postmenopausal breast cancer patients with letroz- ole: a randomized double-blind multicenter study. Ann Oncol 12: 1527–1532.

• IMPACT - Smith IE, Dowsett M, Ebbs SR et al (2005) Neoadjuvant treat- ment of postmenopausal breast cancer with anastrozole, tamoxifen, or both in combination: the immediate preoperative anastrozole, tamoxifen, or combined with tamoxifen (IMPACT) multicenter double-blind randomized trial. J Clin Oncol 23:5108– 5116

• PROACT - Cataliotti L, Buzdar AU, Noguchi S et al (2006) Comparison of anastrozole versus tamoxifen as preoperative therapy in post- menopausal women with hormone receptor-positive breast cancer: the pre-operative ‘‘Arimidex’’ compared to tamoxifen (PROACT) trial. Cancer 106:2095–2103

• Semiglazov V, Kletsel A, Semiglazov V et al (2005) Exemestane vs tamoxifen as neoadjuvant endocrine therapy for postmenopausal women with ER? breast cancer (T2N1–2, T3N01, T4N0M0). J Clin Oncol 23(suppl 16):11s

Preoperative Endocrine Therapy: Tamoxifen Compared with Aromatase Inhibitors Study P024 IMPACT Semiglazov PROACT

Drug(s) LET TAM ANA TAM ANA+ TAM

EXE TAM ANA TAM

Duration 16 wks. 12 wks. 16 wks. 12 wks.

No. of pts. 154 170 113 108 109 36 37 163 151

Response rate (%)

55 36 37 36 39 89 57 50 40

BCS (%) 45 35 46 22 26 39 11 47 38

• P024 - Letrozole was more effective than tamoxifen in postmenopausal women with untreated HR+ breast cancer who were not considered to be candidates for breast-conserving surgery (BCS) at baseline

• In the subset of women considered ineligible for BCS at study entry, letrozole significantly improved the rate of BCS compared with tamoxifen (35 vs. 25%; P = 0.022), but anastrozole did not (44 vs. 31%; P = 0.23)

• In contrast, no significant benefits in objective response rate were observed with anastrozole over tamoxifen, administered for 3 months prior to surgery in a similar patient population – IMPACT & PROACT

• Exemestane is also at least as effective as tamoxifen as neoadjuvant therapy for early disease

Endocrine therapy in Metastatic Breast Cancer

Selection of patient & Rx

Site % ORLocal recurrence 12%

Opposite breast 10%Opposite axilla 10%Bone (osteolytic) 40%

Bone (osteoblastic) 30%Lung 15%

Liver 11%Brain 2%Soft tissue 15%Neck nodes 13%

Premenopausal

Ovarian Ablation

Postmenopausal

Tamoxifen AIsResistance

Fulvestrant / Progestins

High dose Estrogen

??

Biological Therapy

Adjuvant therapeutic strategies

• HER 2 Blockade• Angiogenesis inhibition• PI3K – mTOR – AKT pathway inhibition• CDK 4/6 Inhibition• PARP Inhibition

Dimitrios Zardavas, Konstantinos Tryfonidis, Theodora Goulioti & Martine Piccart (2016): Targeted adjuvant therapy in breast cancer, Expert Review of Anticancer Therapy , October, 2016

The HER Family of Receptors

HER1EGFR HER2 HER3 HER4

Tumor Cell

•Trastuzumab (Herceptin)•Pertuzumab (Omnitarg)

•Lapatinib

•Erlotinib (Tarceva)•Gefitinib (Iressa)•Cetuximab (Erbitux)

Her2/Neu and Breast Cancer

Benign epithelial cells: 20,000 Her2 ReceptorsHer2+ve BrCa cells: 2 million Her2 Receptors

Her2/Neu expression Breast Cancer, overall: 20 – 25%High Grade DCIS: 60 - 70%

Shortened Median SurvivalHER 2/Neu +ve: 3 yrsHER 2/Neu -ve 6 - 7 yrs

Trastuzumab : Response only in Her2+ve cases • Slamon et.al. , NEJM, 2001:

significant benefit of Herceptin added to Taxol (Paclitaxel) in stage IV disease

• Adjuvant studies (NSABP, BCIRG, HERA, FinHER)

Adjuvant Trastuzumab Therapy for HER2-overexpressing Breast Cancer

• In 2005, reports from 4 major RCTs that examined the addition of Trastuzumab to chemotherapy as adjuvant treatment

Adjuvant Trastuzumab TrialsNSABP B-31

NCCTG 9831

H…x 52

H…x 52

H…x 52

H…x 52

H…x 52

BCIRG 006

H…x 1 years

H…x 2 years

No therapy

StandardChemo Rx

HERA

Adjuvant Trials of Trastuzumab

Trial No. of patients Chemotherapy regimen

Trastuzumab Regimen

NSABP B-31/NCCTG N9831

3351 AC -> P 1 yr beginning concurrently with P

HERA 3401 AC orAC-> T

1 yr beginning sequentially after chemotherapy

FinHER 232 V or D -> FEC 9 wk beginning concurrently with V or D

BCIRG 006 3222 AC -> TCarbo+T

1 yr beginning concurrently with T/Carbo+T

BCIRG 006

• 3222 pts• HER2neu+, early breast cancer• Median FU – 65 mnths

• No DFS or OS differences between Trastuzumab arms• Both Trastuzumab arms superior to AC-T arms• AC-T+H > TCH (significant) – for side effects CHF, cardiac symptoms• Trastuzumab reduces the risk of recurrence over chemotherapy by 39%

AC-T AC-TH TCH

DFS 75% 84% 81%

OS 87% 92% 91%

HERA

• 2-yr DFS advantage – 8.4% with Trastuzumab• No OS difference between Trastuzumab vs No trastuzumab• More cardiotoxicity• 1 yr Trastuzumab Improves DFS & RFS significantly• Trastuzumab reduces the risk of recurrence over chemotherapy by 46%

• 1010 pts with axillary node+ve/high risk node-ve• 3 cycles Docetaxel/Vinorelbine -> 3 FEC• 232 Her2+• Median FU – 36 mth• Primary end point - RFS

FinHER

For all patient Docetaxel/ Vinorelbine

Docetaxel Vinorelbine

RFS 91% 86% P – 0.005

For 232 HER2neu+ Pts Trastuzumab No Trastuzumab

RFS 89% 78% P – 0.01

Trastuzumab reduces the risk of recurrence over chemotherapy by 58%

NSABP B-31/NCCTG 9831

• 3351• Compared AC->T +/- Trastuzumab

NSABP B-31

NCCTG N9831

Arm 1Arm 2

Arm A

Arm BArm C

= doxorubicin/cyclophosphamide (AC) 60/600 mg/m2 q 3 wk x 4= paclitaxel (T) 175 mg/m2 q 3 wk x 4= paclitaxel (T) 80 mg/m2/wk x 12= trastuzumab (H) 4mg/kg LD + 2 mg/kg/wk x 51

Control: ACT

Investigational: ACT+H

Trastuzumab reduces the risk of recurrence over chemotherapy by 48% and the risk of death by 31%

PHARE

• Median FU – 42 mnths• 1691 patients were randomly assigned to receive 12 months of trastuzumab and 1693 to receive 6

months of trastuzumab • Primary endpoint was disease-free survival • HER2-positive early breast cancer who had received at least four cycles of chemotherapy, had

breast-axillary surgery, and had received up to 6 months of trastuzumab • Patients were scheduled to be randomised after 6 months of trastuzumab treatment to either

continuation for another 6 months or to discontinue

• 6 mth Trastuzumab was non-inferior to 12 mth Trastuzumab

• The standard treatment should remain as 12 months of adjuvant trastuzumab.

• Significantly more patients in the 12-month group experienced a cardiac event than did those in the 6-month group (96 [5·7%] of 1690 patients vs 32 [1·9%] of 1690 patients, p<0·0001).

Trastuzumab in Neo-adjuvant setting

• HER2-positive locally advanced or inflammatory breast cancer • 228 patients • neoadjuvant chemotherapy alone or with 1 year of trastuzumab (concurrently with

neoadjuvant chemotherapy and continued after surgery) • primary endpoint was event-free survival• Median FU – 5.4 yrs

D

• Event-free survival was strongly associated with pathological complete remission in patients given trastuzumab.

Adjuvant therapeutic strategies

• HER 2 Blockade• Angiogenesis inhibition• PI3K – mTOR – AKT pathway inhibition• CDK 4/6 Inhibition• PARP Inhibition

Single agent HER2 blockade

• Neratinib –metastatic setting• ExteNET (Extended Neratinib)

• Trastuzumab-DM1 (Antibody drug conjugate) –USFDA approved 2nd line in Metastatic Breast Ca

• EMILIA• KATHERINE : Trastuzumab-DM1 vs Trastuzumab

Dual HER 2 Bloackade

• Trastuzumab is the backbone of all dual HER2 blockade therapies

• Lapatinib - reversible EGFR/HER2 tyrosine kinase inhibitor (TKI) • Neo-ALTTO• CHER-LOB• CALGB 40601• NSABP-B41• TBCRC006 studies

• Pertuzumab - humanized anti- HER2 mAb blocking the dimerization of HER2 with other HER family receptors

• NeoSphere• TRYPHAENA • APHINITY

Newer Molecules

• LAPATINIB

• PERTUZUMAB

ALTTO

• 8381 patients with HER2- positive early breast cancer• Randomly assigned to either trastuzumab, lapatinib, trastuzumab followed by lapatinib, or their

combination• Dual targeting of HER2 with lapatinib and trastuzumab did not significantly improve disease-free or

overall survival compared with trastuzumab after a median follow-up of 4·5 yrs• No statistically significant difference in overall survival with dual [concomitant] blockade, or sequential

anti-HER2 treatment, vs single-agent trastuzumab

• Trastuzumab and the tyrosine kinase inhibitor lapatinib have complementary mechanisms of action and synergistic antitumour activity in models of HER2-overexpressing breast cancer.

• 3 arms :- oral lapatinib (1500 mg), intravenous trastuzumab (loading dose 4 mg/kg, subsequent doses 2 mg/kg), or lapatinib (1000 mg) plus trastuzumab

• Primary endpoint was the rate of pathological complete response (pCR) • 154 patients received lapatinib, 149 trastuzumab, and 152 the combination

HER2 Therapy CombinationsNeo ALTTO: Preop HER2+Baselga J et al, Lancet 379:633-640, 2012

Invasive, operableHER2+ breast

cancerT > 2 cm

N=450

lapatinib

trastuzumab

lapatinibtrastuzumab

FEC

X

3

SURGERY

RANDOMIZE

Lapatinib 1500 mg/d

Trastuzumab weekly

Lapatinib 1000 to 750trastuzumab

paclitaxel 80 mg/m2

paclitaxel

paclitaxel

pCR

• Cleopatra Study -2013, 2015• Pertuzumab• Median FU-49.5 mth• 808 pts• metastatic breast cancer who had not received previous chemotherapy or anti-HER2 therapy for

their metastatic disease to receive the pertuzumab combination or the placebo combination

• PFS was significantly improved after first-line therapy with pertuzumab, trastuzumab, and docetaxel, as compared with placebo, trastuzumab, and docetaxel.

• Overall survival was significantly improved with pertuzumab to 56.5 mth• First-line therapy with pertuzumab, trastuzumab, and docetaxel significantly improved

overall survival among patients with HER2-positive metastatic breast cancer

Angiogenesis Inhibition• Bevacizumab - mAb targeting vascular endothelial growth factor A

(VEGF-A) • Metastatic Breast Cancer

• BEATRICE • BETH (Bevacizumab with Trastuzumab Adjuvant Therapy in HER2+ Breast

Cancer) • NSABP B-40

• Based on these results, bevacizumab cannot be currently recommended as part of the adjuvant systemic treatment for patients with early-stage BC

ADJUVANT PI3K – mTOR – AKT pathway inhibition

• Everolimus

• BOLERO 1 - Trastuzumab + Paclitaxel +/- Everolimus• BOLERO 3 – Everolimus + Vinorelbine +/- Trastuzumab

ADJUVANT CDK4/6 INHIBITION

• Palbociclib – FDA approved in the metastatic ER+/HER2Neu –ve BC

• PALOMA-1 - Pablociclib + Letrozole vs Letrozole (PFS improvement)• PALOMA-3 - Palbociclib + Fulvestrant vs Fulvestrant (PFS improvement)• PALLAS - ongoing

ADJUVANT PARP INHIBITION

• Olaparib

• Olympia - Patients with germline BRCA1/2 mutations and high-risk HER2-negative BC

Cardiotoxicity

Cardiotoxicity

• The incidence is about 4% when the dose of doxorubicin is 500–550 mg/m2, 18% when the dose is 551–600 mg/m2 and 36% when the dose exceeds 600 mg/m2

• Doxorubicin can induce cardiotoxicity, particularly at cumulative doses more than 300 mg/m2

• While patients with preexisting left ventricular dysfunction are at increased risk of developing anthracycline-induced cardiotoxicity, at least one study suggests that significant decreases in LVEF from the baseline value do not occur for cumulative doses up to 350 mg/m2

• 5-FU - Cardiotoxicity incidence ranges from 1% to 68% in the literature (>800 mg/m2)• Incidence of Cardiotoxicity with cyclophosphamide therapy ranges from 7% to 28%; the risk of

cardiotoxicity is dose related (>150 mg/kg and 1.5 g/m2/day)• LVEF <54% is identified as a risk factor for development of HF in patients undergoing treatment

with trastuzumab• No increase in cardiac events or serious side effects by combined use of trastuzumab and radiation

Lefrak EA, Pitha J, Rosenheim S, Gottlieb JA. A clinicopathologic analysis of Adriamycin cardiotoxicity. Cancer. 1973;32:302–314Choi BW, Berger HJ, Schwartz PE, et al. Serial radionuclide assessment of doxorubicin cardiotoxicity in cancer patients with abnormal baseline resting left ventricular performance. Am Heart J. 1983;106(4 Pt 1 ):638–43

Incidence of cardiotoxicity with combined use• Incidence of CHF in the randomized study was• 11% - Paclitaxel +Trastuzumab• 1% - Paclitaxel alone

• Trastuzumab alone – 7%

• AC – 7%• AC + Trastuzumab – 28%

• The incidence of trastuzumab-related HF is 2%–7%; it increases with age >50 years, border-line LVEF before treatment, history of CVD and prior treatment with anthracycline and it rises to 27% when trastuzumab is used concurrently with anthracycline plus cyclophosphamide.

• Unlike Anthacycline, trastuzumab toxicity is not dose related, and it is frequently reversible

Perez EA: Paclitaxel and cardiotoxicity. J Clin Oncol 16:3481- 3482, 1998 Herceptin package insert. South San Francisco, CA, Genentech, Inc, 1998 Transcript of proceedings, Department of Health and Human Services, Food and Drug Administration Oncologic Drugs Advisory Committee, Volume 2, September 2, 1998, pp 232-414

Incidence of Cardiotoxicity• 1% - Paclitaxel monotherapy• 4% - Trastuzumab montherapy• 8% - AC• 27% - AC + Trastuzumab

Keefe et al., Trastuzumab associated cardiotoxicity; Cancer; Sep 2002

Summary

• Breast cancer is best treated by multi-modality treatment• Combination of Sx + RT + CT + ET + Targeted therapy• Adjuvant CT > Neo-adjuvant CT• 5 yrs Tamoxifen equi-efficaious as AIs for ER+ve cases • 1-yr Trastuzumab is still the best available option in HER2+ve cases

Thank You

Newer agents

• Neo-adjuvant• Neo ALTTO - Trastuzumab + Lapatinib• Neo Sphere - Trastuzumab + Pertuzumab• CHER-LOB – Trastuzunab vs Lapatinib vs Trastuzumab + Lapatinib

• Adjuvant• ALTTO - Trastuzumab + Lapatinib• APHINITY - Trastuzumab + Pertuzumab

• Meastatic• CLEOPATRA - Trastuzumab + Pertuzumab• PHEREXA - Trastuzumab + Pertuzumab + Capecitabine• VELVET - Trastuzumab + Pertuzumab + Vinorelbine• MARIANNE - TDM 1 + Pertuzumab• BOLERO 1 - Trastuzumab + Paclitaxel +/- Everolimus• BOLERO 3 – Everolimus + Vinorelbine +/- Trastuzumab • MM-111 + Trastuzumab and/or Lapatinib